Lupowitz Z, Rimler A, Zisapel N
Department of Neurobiochemistry, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Israel.
Cell Mol Life Sci. 2001 Dec;58(14):2129-35. doi: 10.1007/PL00000842.
The intracellular signaling pathways mediating the nuclear exclusion of the androgen receptor (AR) by melatonin were evaluated in PC3 cells stably transfected with the AR. The melatonin-induced nuclear exclusion of the AR by melatonin (100 nM, 3 h) was blocked by LY 83583 (an inhibitor of guanylyl cyclases). 8-Bromo-cGMP (a cell-permeable cGMP analog), mimicked the effect of melatonin, as did ionomycin (a calcium ionophore) and PMA [an activator of protein kinase C (PKC)], and their effects were blocked by GF- 109203X (a selective PKC inhibitor). BAPTA (an intracellular calcium chelator) blocked the effects of melatonin and 8-bromo-cGMP but not of PMA. Inhibition or activation of the protein kinase A pathway did not affect basal or melatonin-mediated AR localization. We conclude that the melatonin-mediated rise in cGMP elicits AR nuclear exclusion via a pathway involving increased intracellular calcium and PKC activation. These results define a novel signaling pathway that regulates AR localization and androgen responses in target cells.
在稳定转染雄激素受体（AR）的PC3细胞中，评估了褪黑素介导AR核排除的细胞内信号通路。LY 83583（鸟苷酸环化酶抑制剂）可阻断褪黑素（100 nM，3小时）诱导的AR核排除。8-溴-cGMP（一种可透过细胞的cGMP类似物）、离子霉素（一种钙离子载体）和PMA[蛋白激酶C（PKC）激活剂]模拟了褪黑素的作用，且它们的作用被GF-109203X（一种选择性PKC抑制剂）阻断。BAPTA（一种细胞内钙螯合剂）阻断了褪黑素和8-溴-cGMP的作用，但未阻断PMA的作用。蛋白激酶A途径的抑制或激活不影响基础或褪黑素介导的AR定位。我们得出结论，褪黑素介导的cGMP升高通过涉及细胞内钙增加和PKC激活的途径引发AR核排除。这些结果定义了一种调节靶细胞中AR定位和雄激素反应的新信号通路。
